Mutagen sensitivity and risk of second cancer in younger adults with head and neck squamous cell cancer: 15-year results.

PURPOSE: To evaluate the mutagen sensitivity phenotype on the risk of second primary cancer (SPC) in patients with head and neck squamous cell carcinoma (HNSCC), and to estimate the long-term rate of SPC and the outcome with SPC. METHODS: A survey was made regarding SPC among 124 younger (≤ 50 years) adults with HNSCC who were enrolled in a pretreatment mutagen sensitivity investigation during 1996-2006. Mutagen sensitivity was assessed by exposing lymphocytes to bleomycin in vitro and quantifying the bleomycin-induced chromatid breaks per cell (b/c). Patients were classified as hypersensitive (> 1 b/c) or not hypersensitive (≤ 1 b/c). RESULTS: Mean follow-up time for all patients was 68 months (range: 5-288 months), and the 15-year cancer-specific survival was 15%. Twenty patients (16%) developed a SPC (15-year estimated rate: 41%), and half of them was hypersensitive. The crude rate of SPC for hypersensitive (n = 65) or not hypersensitive (n = 59) patients were 15 and 17%, respectively (p = 0.4272). The 15-year estimated rate of SPC for hypersensitive and not hypersensitive patients was 36 and 48%, respectively (p = 0.3743). Gender, UICC stages, anatomical sites of index cancer did not prove to be a significant risk factor for SPC. Forty-five percent of SPC developed after the 10-year follow-up. The 3­year cancer-specific survival was 23% with SPC. CONCLUSION: According to our findings, mutagen hypersensitivity was not associated with an increased SPC risk in HNSCC patients. Patients are at a lifelong risk of developing a SPC. Survival with SPC is very poor.

In vivo validation of spatio-temporal liver motion prediction from motion tracked on MR thermometry images.

PURPOSE: Magnetic resonance-guided focused ultrasound (MRgFUS) of the liver during free-breathing requires spatio-temporal prediction of the liver motion from partial motion observations. The study purpose is to evaluate the prediction accuracy for a realistic MRgFUS therapy scenario, namely for human in vivo data, tracking based on MR images routinely acquired during MRgFUS and in vivo deformations caused by the FUS probe. METHODS: In vivo validation of the motion model was based on a 3D breath-hold image and an interleaved acquisition of two MR slices. Prediction accuracy was determined with respect to manually annotated landmarks. A statistical population liver motion model was used for predicting the liver motion for not tracked regions. This model was individualized by mapping it to end-exhale 3D breath-hold images. Spatial correspondence between tracking and model positions was established by affine 3D-to-2D image registration. For spatio-temporal prediction, MR tracking results were temporally extrapolated. RESULTS: Performance was evaluated for 10 volunteers, of which 5 had a dummy FUS probe put on their abdomen. MR tracking had a mean (95 %) accuracy of 1.1 (2.4) mm. The motion of the liver on the evaluation MR slice was spatio-temporally predicted with an accuracy of 1.9 (4.4) mm for a latency of 216 ms. A simple translation model performed similarly (2.1 (4.8) mm) as the two MR slices were relatively close (mean 38 mm). Temporal prediction was important (10 % error reduction), while registration effects could only partially be assessed and showed no benefits. On average, motion magnitude, motion amplitude and breathing frequency increased by 24, 16 and 8 %, respectively, for the cases with FUS probe placement. This motion increase could be reduced by the spatio-temporal prediction. CONCLUSION: The study shows that tracking liver vessels on MR images, which are also used for MR thermometry, is a viable approach.

Comparative evaluation of support vector machine classification for computer aided detection of breast masses in mammography.

False positive (FP) marks represent an obstacle for effective use of computer-aided detection (CADe) of breast masses in mammography. Typically, the problem can be approached either by developing more discriminative features or by employing different classifier designs. In this paper, the usage of support vector machine (SVM) classification for FP reduction in CADe is investigated, presenting a systematic quantitative evaluation against neural networks, k-nearest neighbor classification, linear discriminant analysis and random forests. A large database of 2516 film mammography examinations and 73 input features was used to train the classifiers and evaluate for their performance on correctly diagnosed exams as well as false negatives. Further, classifier robustness was investigated using varying training data and feature sets as input. The evaluation was based on the mean exam sensitivity in 0.05-1 FPs on normals on the free-response receiver operating characteristic curve (FROC), incorporated into a tenfold cross validation framework. It was found that SVM classification using a Gaussian kernel offered significantly increased detection performance (P = 0.0002) compared to the reference methods. Varying training data and input features, SVMs showed improved exploitation of large feature sets. It is concluded that with the SVM-based CADe a significant reduction of FPs is possible outperforming other state-of-the-art approaches for breast mass CADe.

Generation of individualized thalamus target maps by using statistical shape models and thalamocortical tractography.

BACKGROUND AND PURPOSE: Neurosurgical interventions of the thalamus rely on transferring stereotactic coordinates from an atlas onto the patient's MR brain images. We propose a prototype application for performing thalamus target map individualization by fusing patient-specific thalamus geometric information and diffusion tensor tractography. MATERIALS AND METHODS: Previously, our workgroup developed a thalamus atlas by fusing anatomic information from 7 histologically processed thalami. Thalamocortical connectivity maps were generated from DTI scans of 40 subjects by using a previously described procedure and were mapped to a standard neuroimaging space. These data were merged into a statistical shape model describing the morphologic variability of the thalamic outline, nuclei, and connectivity landmarks. This model was used to deform the atlas to individual images. Postmortem MR imaging scans were used to quantify the accuracy of nuclei predictions. RESULTS: Reliable tractography-based markers were located in the ventral lateral thalamus, with the somatosensory connections coinciding with the VPLa and VPLp nuclei; and motor/premotor connections, with the VLpv and VLa nuclei. Prediction accuracy of thalamus outlines was higher with the SSM approach than the ACPC alignment of data (0.56 mm versus 1.24; Dice overlap: 0.87 versus 0.7); for individual nuclei: 0.65 mm, Dice: 0.63 (SSM); 1.24 mm, Dice: 0.4 (ACPC). CONCLUSIONS: Previous studies have already applied DTI to the thalamus. As a further step in this direction, we demonstrate a hybrid approach by using statistical shape models, which have the potential to cope with intersubject variations in individual thalamus geometry.

Keep breathing! Common motion helps multi-modal mapping.

We propose an unconventional approach for transferring of information between multi-modal images. It exploits the temporal commonality of multi-modal images acquired from the same organ during free-breathing. Strikingly there is no need for capturing the same region by the modalities. The method is based on extracting a low-dimensional description of the image sequences, selecting the common cause signal (breathing) for both modalities and finding the most similar sub-sequences for predicting image feature location. The approach was evaluated for 3 volunteers on sequences of 2D MRI and 2D US images of the liver acquired at different locations. Simultaneous acquisition of these images allowed for quantitative evaluation (predicted versus ground truth MRI feature locations). The best performance was achieved with signal extraction by slow feature analysis resulting in an average error of 2.6 mm (4.2 mm) for sequences acquired at the same (a different) time.

Intensity-based elastic registration incorporating anisotropic landmark errors and rotational information.

PURPOSE: Thin-plate splines (TPS) represent an effective tool for estimating the deformation that warps one set of landmarks to another based on the physical equivalent of thin metal sheets. In the original formulation, data used to estimate the deformation field are restricted to landmark locations only and thus does not allow to incorporate information about the rotation of the image around the landmark. It furthermore assumes that landmark positions are known exactly which is not the case in real world applications. These localization inaccuracies are propagated to the entire deformation field as each landmark has a global influence. We propose to use a TPS approximation method that incorporates anisotropic landmark errors and rotational information and integrate it into a hierarchical elastic registration framework (HERA). The improvement of the registration performance has been evaluated. METHODS: The proposed TPS approximation scheme integrates anisotropic landmark errors with rotational information of the landmarks. The anisotropic landmark errors are represented by their covariance matrices estimated directly from the image data as a minimal stochastic localization error, i.e. the Cramér-Rao bound. The rotational attribute of each landmark is characterized by an additional angular landmark, thus doubling the number of landmarks in the TPS model. This allows the TPS approximation to better cope up with local deformations. RESULTS: We integrated the proposed TPS approach into the HERA registration framework and applied it to register 161 image pairs from a digital mammogram database. Experiments showed that the mean squared error using the proposed TPS approximation was superior to pure TPS interpolation. On artificially deformed breast images HERA, with the proposed TPS approximation, performed significantly better than the state-of-the-art registration method presented by Rueckert. CONCLUSION: The TPS approximation approach proposed in this publication allows to incorporate anisotropic landmark errors as well as rotational information. The integration of the method into an intensity-based hierarchical non-rigid registration framework is straightforward and improved the registration quality significantly.

A morphological approach to the simulation of forearm motion.

Computer-based simulations support surgeons in preoperative planning of osteotomy and assessing the improvement of the forearm motion. To this end, an in-silico model of patient-specific forearm kinematics is required. In this paper we introduce a motion model of the forearm which is based on a patient's joint morphology, the form and shape of the joints. The morphology of the articulations is represented by 3-dimensional splines. In this way the gliding motion of the articulations is expressed analytically in a closed-form. Our algorithm was designed to work with available clinical planning data and requires minimal user interaction. This allows an integration in computer-aided planning systems that are operated by surgeons. The accuracy of the simulation results is verified via cadaver experiments.

Measurement, simulation and uncertainty assessment of implant heating during MRI.

The heating of tissues around implants during MRI can pose severe health risks, and careful evaluation is required for leads to be labeled as MR conditionally safe. A recent interlaboratory comparison study has shown that different groups can produce widely varying results (sometimes with more than a factor of 5 difference) when performing measurements according to current guidelines. To determine the related difficulties and to derive optimized procedures, two different generic lead structures have been investigated in this study by using state-of-the-art temperature and dosimetric probes, as well as simulations for which detailed uncertainty budgets have been determined. The agreement between simulations and measurements is well within the combined uncertainty. The study revealed that the uncertainty can be kept below 17% if appropriate instrumentation and procedures are applied. Optimized experimental assessment techniques can be derived from the findings presented herein.

Data-Driven Haptic Rendering-From Viscous Fluids to Visco-Elastic Solids.

In this article we present extensions of our earlier work on data-driven haptic rendering. Haptic feedback is generated directly by interpolating measured data. The selection of appropriate data dimensions is guided by the structure of the generalized Maxwell model. Material elasticity and viscosity are reproduced, including transient material effects like stress relaxation. All these properties can be nonlinear and mutually dependent. Besides visco-elastic bodies, we also apply our method to viscous fluids. We present results for several materials and compare the errors of the interpolated forces with perceptual thresholds reported in the literature. Moreover, we examine how these errors behave if different subjects perform the recordings on which the data-driven haptic feedback is based.

Exploring the use of proper orthogonal decomposition for enhancing blood flow images via computational fluid dynamics.

Obtaining high quality patient-specific flow velocity information is not an easy task. Available clinical data are usually poorly resolved and contain a significant amount of noise. We propose a novel approach to integrate computational fluid dynamics with measurement data to overcome this difficulty. By performing a proper orthogonal decomposition of simulated blood flow patterns for a given vascular location with various anatomical configurations it is possible to obtain a basis model for flow reconstruction. This is used to interpolate imaging data intelligently without having to perform a full flow simulation for each individual patient. This work focuses on assessing the feasibility of such a method.

Technical note: standardized and semiautomated Harris lines detection.

Arrest in long bone growth and the subsequent resumption of growth may be visible as radiopaque transverse lines in radiographs (Harris lines, HL; Harris, HA. 1933. Bone growth in health and disease. London: Oxford University Press). The assessment of individual age at occurrence of such lines, as part of paleopathological skeletal studies, is time-consuming and shows large intra- and interobserver variability. Thus, a standardized, automated detection algorithm would help to increase the validity of such paleopathological research. We present an image analysis application facilitating automatic detection of HL. On the basis of established age calculation methods, the individual age-at-formation can be automatically assessed with the tool presented. Additional user input to confirm the automatic result is possible via an intuitive graphical user interface. Automated detection of HL from digital radiographs of a sample of late Medieval Swiss tibiae was compared to the consensus of manual assessment by two blinded expert observers. The intra- and interobserver variability was high. The quality of the observer result improved when standardized detection criteria were defined and applied. The newly developed algorithm detected two-thirds of the HL that were identified as consensus lines between the observers. It was, however, necessary to validate the last one-third by manual editing. The lack of a large test series must be noted. The application is freely available for further testing by any interested researcher.

Modeling intravasation of liquid distension media in surgical simulators.

During therapeutic hysteroscopy and transurethral resection of the prostate, intravasation of the liquid distension media into the vascular system of the patient occurs. We present a model which allows the integration of the intravasation process into surgical simulator systems. A linear network flow model is extended with a correction for non-Newtonian blood behavior in small vessels and an appropriate handling of vessel compliance. We employ a fast lookup scheme in order to allow for real-time simulation. Cutting of tissue is accounted for by adjusting pressure boundary conditions for all cut vessels. We investigate the influence of changing distention fluid pressure settings and of the position of tissue cuts. In addition, we quantify the intravasation occurring with different approaches of fluid control, and we compare the performance of direct and iterative solvers applied to the non-linear system of the compliant model. Our simulation predicts significant intravasation only on the venous side, and just in cases when larger veins are cut. The implemented methods allow the realistic control of bleeding for short-term and of the total resulting intravasation volume for long-term complication scenarios. While the simulation is fast enough to support real-time training, it is also adequate for explaining intravasation effects which were previously observed on a phenomenological level only.

Interactive visuo-haptic surgical planning tool for pelvic and acetabular fractures.

Treatment of pelvic and acetabular fractures still poses a major challenge to trauma surgeons. We present a tool for intervention planning for such injuries using patient-specific models built from Computed Tomography data. The presented tool has three main parts: (1) the virtual reduction of the bone fragments, (2) the virtual adaptation of the osteosynthesis implants and (3) Finite Element Analysis (FEA) for testing mechanical behavior of the resulting intervention plan. Our tool provides an intuitive visuo-hapic interface designed to be used by trauma surgeons. The type and size of the osteosynthesis material can be determined and measurements like distances and angles relative to landmarks can be taken. First results of prospectively planned interventions show an excellent correlation and a significant gain in operation time.

Epidural malignant lymphomas of the spine: collected experiences with epidural malignant lymphomas of the spinal canal and their treatment.

STUDY DESIGN: Retrospective study of 13 patients treated by the authors. OBJECTIVE: To examine the course of the disease of malignant lymphoma (ML) presenting in the epidural area of the spine. SETTING: Department of Neurosurgery, Third Department of Internal Medicine, Medical and Health Science Center, University of Debrecen, Debrecen, Hungary. SUBJECTS AND METHODS: The epidural presentation in eight patients was heralded by motor signs (paraparesis and plegia), in one by a lesion of the posterior columns of the spinal cord (ataxia), and in three by pain. One patient was free of complaints and symptoms. The affected epidural area was diagnosed previously by myelography and computerized tomography (CT), and later by magnetic resonance (MR), over the course of which the location was verified as thoracic in eight patients, cervical in one, and lumbar in four. The authors recommended surgical intervention in 9 out of 13 cases, in seven cases of Hodgkin's and six cases of non-Hodgkin's lymphoma. Seven patients were treated for recognized manifestations of malignant lymphoma while six were diagnosed by intraoperative-histological examination. RESULTS AND CONCLUSION: The decompression operations for tumors resulted in limited improvement in seven patients (reduction in pain and return of ability to walk). Four patients were not operated on, two of which had significant improvement in their neurological symptoms. Paraparesis remained unchanged in one patient. One patient remained symptom-free. The authors emphasize the importance of interdisciplinary consultation and weighing individual priorities in the indications for operation on epidural ML.

Non-rigid registration of multi-modal images using both mutual information and cross-correlation.

The hierarchical subdivision strategy which decomposes a non-rigid matching problem into numerous local rigid transformations is a very common approach in image registration. While mutual information (MI) has proven to be a very robust and reliable similarity measure for intensity-based matching of multi-modal images, numerous problems have to be faced if it is applied to small-sized images, compromising its usefulness for such subdivision schemes. We examine and explain the loss of MI's statistical consistency along the hierarchical subdivision. Information theoretical measures are proposed to identify the problematic regions in order to overcome the MI drawbacks. This does not only improve the accuracy and robustness of the registration, but also can be used as a very efficient stopping criterion for the further subdivision of nodes in the hierarchy, which drastically reduces the computational cost of the entire registration procedure. Moreover, we present a new intensity mapping technique allowing to replace MI by more reliable measures for small patches. Integrated into the hierarchical framework, this mapping can locally transform the multi-modal images into an intermediate pseudo-modality. This intensity mapping uses the local joint intensity histograms of the coarsely registered sub-images and allows the use of the more robust and computationally more efficient cross-correlation coefficient (CC) for the matching at lower levels of the hierarchy.

Inter-subject modelling of liver deformation during radiation therapy.

This paper presents a statistical model of the liver deformation that occurs in addition to the quasi-periodic respiratory motion. Having an elastic but still compact model of this variability is an important step towards reliable targeting in radiation therapy. To build this model, the deformation of the liver at exhalation was determined for 12 volunteers over roughly one hour using 4DMRI and subsequent non-rigid registration. The correspondence between subjects was established based on mechanically relevant landmarks on the liver surface. Leave-one-out experiments were performed to evaluate the accuracy in predicting the liver deformation from partial information, such as a point tracked by ultrasound imaging. Already predictions from a single point strongly reduced the localisation errors, whilst the method is robust with respect to the exact choice of the measured predictor.

Modelling intravasation of liquid distension media in surgical simulators.

We simulate the intravasation of liquid distention media into the systemic circulation as it occurs during hysteroscopy and transurethral resection of the prostate. A linear network flow model is extended with a correction for non-newtonian blood behaviour in small vessels and an appropriate handling of vessel compliance. We then integrate a fast lookup scheme in order to allow for real-time simulation. Cutting of tissue is accounted for by adjusting pressure boundary conditions for all cut vessels. We investigate the influence of changing distention fluid pressure settings and of the position of tissue cuts. Our simulation predicts significant intravasation only on the venous side, and just in cases when larger veins are cut. The implemented methods allow the realistic control of bleeding for short-term and the total resulting intravasation volume for long-term complication scenarios. While the simulation is fast enough to support real-time training, it is also adequate for explaining intravasation effects which were previously observed on a phenomenological level only.

Using statistical shape analysis for the determination of uterine deformation states during hydrometra.

A fundamental prerequisite of hysteroscopy is the proper distension of the uterine cavity with a fluid, also known as hydrometra. For a virtual reality based simulation of hysteroscopy, the uterus deformation process due to different pressure settings has to be modeled. In previous work we have introduced a hybrid method, which relies on precomputed deformation states to derive the hydrometra changes during runtime. However, new offline computations were necessary for every newly introduced organ mesh. This is not viable if a new surgical scene is to be generated for every training session. Therefore, we include the deformation states during hydrometra into our previously developed statistical shape model for undeformed organ instances. This allows deriving the hydrometra steps together with new undeformed uterus meshes. These can then be used during the interactive simulation for predicting uterus deformation without time-intensive precomputation steps.

4D MR imaging of respiratory organ motion and its variability.

This paper describes a method for 4D imaging, which is used to study respiratory organ motion, a key problem in various treatments. Whilst the commonly used imaging methods rely on simplified breathing patterns to acquire one breathing cycle, the proposed method was developed to study irregularities in organ motion during free breathing over tens of minutes. The method does not assume a constant breathing depth or even strict periodicity and does not depend on an external respiratory signal. Time-resolved 3D image sequences were reconstructed by retrospective stacking of dynamic 2D images using internal image-based sorting. The generic method is demonstrated for the liver and for the lung. Quantitative evaluations of the volume consistency show the advantages over one-dimensional measurements for image sorting. Dense deformation fields describing the respiratory motion were estimated from the reconstructed volumes using non-rigid 3D registration. All obtained motion fields showed variations in the range of minutes such as drifts and deformations, which changed both the exhalation position of the liver and the breathing pattern. The obtained motion data are used in proton therapy planning to evaluate dose delivery methodologies with respect to their motion sensitivity. Besides this application, the new possibilities of studying respiratory motion are valuable for other applications such as the evaluation of gating techniques with respect to residual motion.

Patient specific simulation and navigation of ventriculoscopic interventions.

In this paper a comprehensive framework for pre-operative planning, procedural skill training, and intraoperative navigation is presented. The goal of this system is to integrate surgical simulation with surgical planning in order to improve the individual treatment of patients. Various surgical approaches and new, more complex procedures can be assessed using a safe and objective platform that will allow the physicians to explore and discuss possible risks and benefits prior to the intervention. A simulation environment extends the pre-operative planning in a natural way, as it allows for direct evaluation of the surgical approach envisioned for each case. In addition, by providing intraoperative navigation based on this simulation, surgeons can carry out the previously optimized plan with higher precision and greater confidence.